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Process for producing optically active ester

a technology of optically active and ester, which is applied in the preparation of carboxylic acid esters, chemistry apparatus and processes, and organic chemistry, etc. it can solve the problems of not being considered an industrially applicable process, not being suited to the production of high-optical purity 2-hydroxybutyric, and being very expensive products. , to achieve the effect of high yield and high optical yield

Inactive Publication Date: 2009-05-07
KOWA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013]As shown in the following reaction scheme:(wherein R represents a C1 to C6 alkyl group or a C7 or C8 aralkyl group; R1 represents a C1 to C12 alkyl group or a phenyl group; and * represents S- or R-absolute configuration), the present inventors have employed an optically active 2,3-epoxybutyric ester (2), which can be supplied in a large amount at comparatively low cost through the enzymatic method, and have studied the effect of Lewis acids on reaction of the 2,3-epoxybutyric ester with a thiol. As a result, the inventors have found that use of scandium trifluoromethanesulfonate or ytterbium trifluoromethanesulfonate, which is a recoverable and recyclable Lewis acid, realizes high-yield production of Compound (3) via regio-selective opening of the epoxy ring (see the Examples hereinbelow), and that an optically active 2-hydroxybutyric ester (1) can be produced in high yield and high optical purity via subsequent desulfurization.
[0016]According to the process of the present invention, an optically active 2-hydroxybutyric ester, which is a useful material for producing pharmaceuticals, pesticides, and industrial products, can be produced in high yield and high optical yield.BEST MODES FOR CARRYING OUT THE INVENTION

Problems solved by technology

These optically active 2-hydroxybutyric esters are commercially available reagents (Aldrich), but are very expensive products.
Thus, the process 1) is not suited for the production of high-optical purity 2-hydroxybutyric ester and is not considered an industrially applicable process.
In addition, a 2-ketobutyric ester is chemically unstable (Non-Patent Document 1) and very expensive, which is problematic.
However, three steps are required for the target product, resulting in low overall yield, and a large amount of solvent is required for reaction and post treatment.
Thus, the process 2) has problematically poor efficiency in terms of production conditions.
In addition, since the process 2) includes a step of forming an unstable diazonium salt, reaction conditions are difficult to control, leading to variation in yield and optical purity of the target product.
However, the 2-acyloxyacrylic ester derivative serving as a starting material is produced through a complicated step, and the process includes preparation of an expensive asymmetric ligand and performing asymmetric reduction under high hydrogen pressure.
Thus, the process 3) is not considered an industrially advantageous process.
However, preparation of an asymmetric ligand of the catalyst requires a very complex.
Depending on a substituent of a reaction substrate, optical purity and chemical yield of the target compound are prone to vary, which is one disadvantage of the process.
The process has problems including a drop in regio-selectivity of ring-opening reaction caused by undesired reaction temperature, water present in the reaction system, etc.
; and unavoidable use of a tin reagent which is stoichiometrically toxic in the subsequent deiodation reaction.
Thus, the process 5) is not considered a useful method.

Method used

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  • Process for producing optically active ester
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  • Process for producing optically active ester

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of n-butyl(S)-2-hydroxy-(S)-3-phenylthiobutyrate

[0043]Scandium trifluoromethanesulfonate [Sc(OTf)3] (311 mg) and thiophenol (0.064 mL) were sequentially added at room temperature to a solution of n-butyl (2S,3R)-2,3-epoxybutyrate (100 mg, 97.3% ee) (product of Osaka Organic Chemical Industry, Ltd.) in methylene chloride (5.0 mL), and the mixture was stirred at the same temperature for 10 hours. The reaction mixture was added to water (20 mL), and extracted with chloroform (20 mL×3). The organic layers were combined, and the combined organic layer was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane / ethyl acetate=5 / 1), to thereby yield colorless oil (117 mg, 95.3%).

[0044]IR(ATR); 3484, 2961, 2933, 2873, 1732, 1645, 1474, 1439, 1380, 1240, 1211, 1129, 1090, 1051, 1024, 951, 747, 692 cm−1.

[0045]1H-NMR (400 MHz, CDCl3) δ; 0.94 (t, J=7 Hz, 3H), 1.27 (d, J=7 Hz, 3H) 1.38 (sext...

example 2

Synthesis of n-butyl(S)-2-hydroxy-(S)-3-phenylthiobutyrate

[0048]Ytterbium trifluoromethanesulfonate [Yb(OTf)3] (196 mg) and thiophenol (0.032 mL) were sequentially added at room temperature to a solution of n-butyl (2S,3R)-2,3-epoxybutyrate (50 mg) in methylene chloride (3.0 mL), and the mixture was stirred at the same temperature for 24 hours. The reaction mixture was added to water (20 mL), and extracted with chloroform (20 mL×3). The organic layers were combined, and the combined organic layer was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was purified through preparative thin-layer chromatography (n-hexane / ethyl acetate=5 / 1), to thereby yield colorless oil (69 mg, 81.3%).

example 3

Synthesis of n-butyl(S)-2-hydroxy-(S)-3-ethylthiobutyrate

[0049]Scandium trifluoromethanesulfonate [Sc(OTf)3] (311 mg) and ethanethiol (0.047 mL) were sequentially added at room temperature to a solution of n-butyl (2S,3R)-2,3-epoxybutyrate (100 mg) in methylene chloride (5.0 mL), and the mixture was stirred at the same temperature for 7 hours. The reaction mixture was added to water (20 mL), and extracted with chloroform (20 mL×3). The organic layers were combined, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane / ethyl acetate=5 / 1), to thereby yield colorless oil (116 mg, 83.4%).

[0050]IR(ATR); 3490, 2962, 2931, 2873, 1732, 1456, 1379, 1260, 1239, 1209, 1130, 1088, 1060, 980, 784, 766, 738, 699 cm−1.

[0051]1H-NMR (400 MHz, CDCl3) δ; 0.95 (t, J=7 Hz, 3H), 1.24 (d, J=7 Hz, 3H), 1.28 (t, J=7 Hz, 3H), 1.40 (sext, J=7 Hz, 2H), 1.63-1.70 (m, 2H), 2.57-2....

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Abstract

A process for producing an optically active 2-hydroxybutyric ester (1), characterized by including reacting an optically active 2,3-epoxybutyric ester (2) with a thiol in the presence of scandium trifluoromethanesulfonate or ytterbium trifluoromethanesulfonate, to thereby produce Compound (3), and subjecting Compound (3) to desulfurization reaction:(wherein R represents a C1 to C6 alkyl group or a C7 or C8 aralkyl group; R1 represents a C1 to C12 alkyl group or a phenyl group; and * represents S- or R-absolute configuration).The present invention provides a process for producing an optically active 2-hydroxybutyric ester at high yield and high optical purity.

Description

TECHNICAL FIELD[0001]The present invention relates to a process for producing an optically active 2-hydroxybutyric ester, which is a useful material for producing pharmaceuticals, pesticides, and industrial products.BACKGROUND ART[0002]Optically active 2-hydroxybutyric esters are compounds useful as a reagent or a starting material for producing pharmaceuticals, pesticides, and industrial products. For example, these esters serve as an important starting material for producing (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, which is a PPARα-selective activating agent and serves as a useful prophylactic and / or therapeutic agent for hyperlipemia, arteriosclerosis, diabetes, diabetes complications, inflammation, heart diseases, etc., and is represented by the following formula (A):(Patent Document 1).[0003]These optically active 2-hydroxybutyric esters are commercially available reagents (Aldrich), but are very expensive products. Hitherto,...

Claims

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Application Information

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IPC IPC(8): C07C69/66
CPCC07B53/00C07B2200/07C07C67/317C07C319/14C07C69/675C07C323/52
Inventor ARAKI, TAKAAKIYAMAZAKI, YUKIYOSHISHIBUYA, KIMIYUKI
Owner KOWA CO LTD
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